In higher organisms, the nuclear hormone receptor superfamily includes approximately a dozen distinct genes that encode zinc finger transcription factors, each of which is specifically activated by binding a ligand such as a steroid, thyroid hormone (T3) or retinoic acid (RA). However, there is an additional, somewhat larger group of cDNAs that encode proteins that do not bind or respond to any known ligand. These members of the superfamily are called orphan receptors. While the role of the better characterized conventional receptors in regulating important processes in developing and adult individuals is becoming clearer, the function of the orphan receptors has been uncertain.
A number of the conventional and orphan members of the superfamily share identical or very similar amino acid sequences in an important region of the first zinc finger. Both genetic analyses and X-ray crystallography indicate that this region, termed the P box, makes sequence specific contacts with the DNA. The conventional receptors in this P box-defined subgroup include those that bind estrogen, vitamin D, T3 and RA, and nearly all of the orphan receptors identified to date also fall into this class. As a consequence of this overlap in binding specificity, many hormone response elements can bind more than one type of receptor. The best characterized of these is the element upstream of the rat growth hormone gene, which can be activated by three different isoforms of the T3 receptor encoded by two different genes and by an unknown number of retinoic acid receptor isoforms encoded by three different genes. While it does not appear to respond to the estrogen receptor or the vitamin D receptor, its response to other members of the subgroup remains uncertain.
Recently the potential complexity of the interactions of the conventional receptors with their response elements has been substantially increased by the demonstration that the three closely related RXR proteins can form heterodimers with the thyroid hormone, retinoic acid and vitamin D receptors. These heterodimers show higher binding affinity for appropriate response elements, and the RXRs are hypothesized to play central roles in signal transduction by all three classes of receptors. The impact on such heterodimers of the binding of the retinoid metabolite 9-cis retinoic acid by the RXRs remains unclear.